Global prevalence and correlates of mpox vaccine acceptance and uptake: a systematic review and meta-analysis

Background Vaccination has been recommended as one of the most potent ways of controlling the mpox (formerly, monkeypox) outbreak, particularly among high-risk groups. Here, we evaluated the prevalence of mpox vaccine acceptance and uptake globally. Methods We searched multiple databases for peer-reviewed studies published in English from May 2022 to 25th November 2023 that evaluated mpox vaccine acceptance and/or uptake. We fit a random-effects model meta-analysis to calculate the pooled mpox vaccine acceptance and uptake rates, with their 95% confidence intervals (CI) across population outcomes. We performed subgroup analyses among the six World Health Organization (WHO) regions (Africa [AFR], Region of the Americas [AMR], South-East Asia Region [SEAR], European Region [EUR], Eastern Mediterranean Region [EMR], and the Western Pacific Region [WPR]), as well as among select population subgroups. Results Of the 2531 studies screened, 61 studies, with a cumulative sample size of 263,857 participants from 87 countries were eligible for inclusion. The overall vaccine acceptance and uptake rates were 59.7% and 30.9% globally. Acceptance and uptake rates among the LGBTQI+ community were 73.6% vs 39.8% globally, 60.9% vs. 37.1% in AMR, 80.9% vs. 50.0% in EUR, and 75.2% vs. 33.5% in WPR. Among PLHIV, vaccine acceptance and uptake rates were 66.4% vs. 35.7% globally, 64.0% vs. 33.9% in AMR, 65.1% vs. 27.0% in EUR, and 69.5% vs. 46.6% in WPR. Among healthcare workers, vaccination intention was 51.0% globally. Conclusions Tailored interventions are needed to bolster confidence in the mpox vaccine, maximize vaccine uptake, and increase vaccine access to close the gaps between acceptance and uptake especially among key populations residing in regions with low rates of acceptance and uptake.

In lines 169-171, combining the acceptance group (intention + uptake) may be a source of heterogeneity.It is advisable to treat these outcomes separately to avoid potential confounding factors.
In the discussion section, please provide a summary of the studies included to provide a concise overview for readers.
In addition to the major comments, I have a few minor suggestions: Please update the figures related to Mpox in the abstract to ensure accuracy.
It would be beneficial to mention the efficacy and generations of vaccines primarily used for smallpox and Mpox.
Although hesitancy is mentioned in the introduction, it is not defined.It would be helpful to provide a clear definition for readers' understanding.
If applicable, I suggest updating the search as more than three months have passed since the initial search was conducted.
In line 157, please clarify why two references were used.
In line 159, please correct the reference by removing the "p" at the end.
please revise the comment on the extraction table ; During the extraction process, Algeria was included in three studies, not two.Although you mentioned two of them, reference 46 also includes Algeria.
Please report the heterogeneity alongside the pooled effect size and confidence interval to provide a comprehensive analysis.
Improve the resolution of the figures to ensure clear visualization.I believe addressing these comments and suggestions will significantly improve the manuscript.
Thank you once again for the opportunity to review this paper.
Reviewer #2 (Remarks to the Author): The article discussing the global acceptance and uptake of the mpox vaccine is undeniably intriguing, offering valuable insights into a crucial aspect of public health.However, I must express my concerns, particularly regarding the statistical analysis/methodology employed in the study.Before considering acceptance for publication, the following concerns must me addressed: 1.In line 72 of the manuscript the authors make a reference to previous studies of vaccination intention in mpox, however, they cite a study carried out for COVID-19.Please make the corresponding corrections 2. In line 161-162 the authors indicate that they used a Freeman-tukey double arcsine transformation to include studies with proportions close to or equal to 1, however, in these cases the correct thing to do is to use a continuity correction and not a variance stabilizer.), is a retrospective cohort, however, when reviewing the section of the manuscript "Critical appraisal (quality assessment) of included studies" and observing the quality assessment scoring table, the authors only used the Newcastle-Ottawa Scale (NOS) for Cross-sectional studies.Please, it is necessary to correct this and evaluate the article in question using a specific scale for cohort studies.
5. In the discussion, the authors should compare the results of their study with previous systematic reviews on vaccination acceptance for mpox.
Reviewer #3 (Remarks to the Author): I would thank the authors for this interesting work.owever, after reviewing, I found some concern that bothered me: 1.The first concern is related to the fact that the authors included some studies conducted in 2020 which could affect the results.In fact, the COVID-19 pandemic has given a new vision of this phenomenon.Also, including 2 studies among 42 could affect the results.2. The second concern is related to the maneer of wrting.In fact, the authors used nearly the same expression (among....) in almost all the results.3. Some spelling errors are also observed (exp: line 16-17: EUR 17.9%; AMR 13.3%; and AFR 5.0%." add the brackets; line 17-18: Acceptance and uptake were 72.0% and 30.1% among the LGBTQI+ community, and healthcare workers (59.8%)" correct please Line 159: delete p3 Line 224-239: the term "by both Begg's test and Egger's test" is repeated multiple times.try to reformulate.Also "p"value should be in ower case (in all the manuscript).The same remark for lines 243-252 and 265-275 (then is repeated multiple times).Try to reformulate please.Also, you do not need to repeat "metaanylysis" in each tile, you can use just: "prevalence...".At last, I suggest to reformulate the title Good luck

REVIEWER 1 COMMENTS
I would like to express my gratitude for the opportunity to review this paper.I would also like to acknowledge the authors for their valuable contributions.Despite the existence of two similar studies, the authors undertook this review to include additional studies and address further objectives related to Mpox vaccination.However, I have several comments to suggest improvements to the quality of this work:

Comment (1)
A significant proportion of the pooled analyses showed substantial heterogeneity, which hindered the interpretation of the findings.I recommend that the authors investigate the sources of this heterogeneity by either rechecking the data extraction process or considering the exclusion of low-quality studies.It would be advisable to avoid pooling studies with different objectives and instead conduct subgroup analyses based on the tools used.Additionally, employing advanced analyses such as Gosg sensitivity analysis and metaregression may provide valuable insights.I suggest referring to the following useful paper for guidance: [https://www.nature.com/articles/s41598-021-04345-x].

Response
We thank the reviewer for this feedback.We want to note that "I 2" is usually known to be high in meta-analyses of proportions (such as in this study where the objective is not to compare two groups but to derive a single summary estimate of the individual proportions reported in the included studies).Barker et al. (2021) -https://doi.org/10.1186/s12874-021-01381-zexplainedas follows: "Although I 2 was developed in the context of comparative data, it is commonly applied to estimate heterogeneity for proportional meta-analysis.In this type of analysis, I 2 is usually high.This can be due to the nature of proportional data, where little variance is observed even in studies with small sample sizes.Moreover, true heterogeneity is expected in prevalence and incidence estimates due to differences in the time and place where included studies were conducted.Therefore, high I 2 in the context of proportional meta-analysis does not necessarily mean that data is inconsistent."Nonetheless, we explored the included studies, per the reviewer's recommendation, to ascertain if the inclusion of low-quality studies may have led to the observed heterogeneity.However, none of the included studies we scored is of a low quality that warrants its exclusion from the analysis.Moreover, just as found in the paper cited by the reviewer, the exclusion of low-quality studies does not necessarily eliminate heterogeneity.Also, we've rechecked our data and ascertained that all included studies conform with our inclusion criteria and have similar objectives with respect to the corresponding study outcomes (intention, uptake, and acceptance [intention + uptake]).further confirmed that the extracted values are accurate.Moreover, we treated each of these outcomes independently and conducted a metaanalysis for each.
On the issue of performing "subgroup analysis based on the tools used," we wish to note that all our study outcomes were defined according to the previous studies on vaccine acceptance, intention, and uptake.
Although some of the included studies used different scales to define the study outcomes, we only used the actual frequencies/proportions of intention/uptake/acceptance from these studies in accordance with our pre-specified outcome definitions.Thus, we defined the prevalence of intention to be vaccinated as the proportion of those who responded " yes" (for a binary question, yes or no) or "yes definitely/yes likely" (for a four-or five-point Likert scale question) to a question asking participants about their willingness to receive the vaccine.We defined uptake prevalence as the proportion of those who received at least one dose of any of the recommended mpox vaccines among the study population, while the prevalence of acceptance was defined as the proportion of those who intend to receive the vaccine and those who have taken at least a single dose among the study population.Also, per the reviewer's feedback, we have expanded the scope of our subgroup analyses for each outcome and evaluated the overall and regional prevalence further stratified by study subpopulations (LGBTQI+ community, health workers, PLHIV, and the general public).This new analysis more deeply explores the potential sources of heterogeneity between the included studies.
We also agree with the reviewer's recommendation for a sensitivity analysis.We have performed a series of leave-one-out meta-analyses for each outcome (overall and stratified by population subgroups, where possible) to assess if the omission of any of the included studies has an overriding influence on the overall estimate.The results of these analyses are presented in the results section of the manuscript.

Comment (2)
The excessive use of abbreviations, especially in the abstract, detracts from readability.It is recommended to limit the use of abbreviations or provide their full forms upon the first mention.

Response
We thank the Reviewer for this feedback.We've re-read the whole manuscript to ascertain that all abbreviations are written in their full forms on the first mention.In addition, we have also created a dictionary of all abbreviations used and added it at the end of the manuscript.

Comment (3)
The authors did not mention how disagreements among the reviewers were resolved or the value of the kappa test of agreement between reviewers.Including this information would enhance transparency and indicate the reliability of the review process.

Response
We thank the Reviewer for this important feedback.We've provided information on how disagreements were resolved on page-9, lines 204-207.Where disputes occurred between the two junior authors (SKS and MSM) critically appraising the studies, we relied on consensus between our two senior authors for a final consensus score (as done in the paper cited by the reviewer).Below is an excerpt from the manuscript detailing how we addressed disagreement: "The scores of the two investigators were compared and reviewed by two senior authors (FIT and ATB), and where disputes occurred, a final consensus score was decided by the senior authors through revision and discussion of the articles together."

Comment (4)
Despite reporting publication bias in only one outcome, the authors did not search the grey literature or include non-published data.It is crucial to consider these additional sources of information to improve the comprehensiveness of the review.

Response
We thank the Reviewer for this suggestion.We've repeated our literature search in the select databases and added three more databases (the Regional Office for Africa Library, the African Index Medicus, and the WHO Institutional Repository for Information Sharing) and also employed forward and backward citation tracking to include studies published by 30th October 2023.However, we did not include preprints, grey literature, and other non-peer-reviewed studies, as suggested by the reviewer, because the Editor required that included studies should be limited to peer-reviewed articles only.We've also revised our inclusion criteria to "include only peer-reviewed publications".
We also wish to highlight that the seven studies that were available as preprints in our initial submission have now all been published as peerreviewed articles.
Below is the list of the seven studies that have now been published as peer-reviewed articles.Furthermore, we wish to note that our updated literature search resulted in the addition of 21 new peer-reviewed studies to the data.Please see

Comment (5)
The authors did not specify whether they conducted a manual search and citation tracking.
Clarifying whether these methods were employed would provide a more comprehensive understanding of the search strategy.

Response
We thank the Reviewer for this important comment.We've employed manual search as well as forward and backward citation tracking to retrieve studies and have included this update to our methods section (page 7/ lines 156-157) and the PRISMA flow diagram for study selection.

Comment (6)
In lines 169-171, combining the acceptance group (intention + uptake) may be a source of heterogeneity.It is advisable to treat these outcomes separately to avoid potential confounding factors.

Response
We thank the Reviewer for this important suggestion.We defined acceptance in accordance with previously published studies ( Moreover, we have performed a separate analysis for intention and uptake.We have more clearly explained this in the methods section (page 10, line 223-231).

Comment (7)
In the discussion section, please provide a summary of the studies included to provide a concise overview for readers.

Response
We thank the Reviewer for this important suggestion.We have added a summary of the included studies at the beginning of the discussion section, as recommended (page 25, lines 589-599).

Minor Comments Comment (8)
Please update the figures related to Mpox in the abstract to ensure accuracy.

Response
We thank the Editor for this important suggestion.We've updated the figures as suggested.Please see the abstract for confirmation.

Comment (9)
It would be beneficial to mention the efficacy and generations of vaccines primarily used for smallpox and Mpox.

Response
We thank the Reviewer for this suggestion.We've added detailed information regarding the approved vaccines in the second paragraph of our introduction, as recommended.We added a comment on the safety, efficacy, and immunogenicity of the mpox vaccines based on the findings of a most recently published systematic review study.
Below is an excerpt from the second paragraph of our introduction section: Vaccination against mpox may be provided to individuals at high risk of the infection as primary preventive vaccination (PPV) before exposure to the mpox virus, or as post-exposure preventive vaccination (PEPV), for contacts of mpox cases. 2,5In addition to the previously employed smallpox vaccine, which is highly effective in protecting against mpox, 11 newer vaccines, including the MVA-BN, LC16, and the ACAM2000 have been approved in many countries for the prevention of mpox. 2,12A recently published systematic review shows that these vaccines are highly effective, safe, and immunogenic depending on the number of doses administered and that vaccines against smallpox offer cross-protection against mpox. 13 Vaccines and immunization for monkeypox: Interim guidance, 16